Intervention of the inflammation cascade with tumor necrosis factor-α (TNF-α) monoclonal antibodies or receptors represents a major approach in clinical immunotherapy against inflammatory diseases. However, this approach often suffers from high cost, autoimmunity to antibodies, and various side effects. siRNA-mediated RNA interference (RNAi) has recently emerged as a potent modality in regulating gene expression by suppressing mRNA translation. Its high efficiency and specificity has made it a promising treatment paradigm for TNF-α-mediated inflammatory disorders. The therapeutic potential of siRNA was recently exemplified by a report of attenuating systemic inflammation by targeting orally delivered Map4k4 siRNA to gut-associated macrophages (GAMs). Owing to the infiltration of GAMs to systemic reticulo-endothelial tissues, Map4k4 siRNA-mediated TNF-α knockdown in GAMs extended to other tissues and thus induced systemic anti-inflammatory effects (Aouadi et al., Nature 2009, 458, 1180).
Despite its biological potency, the clinical potential of orally delivered siRNA has been hampered by the lack of efficient delivery technologies. siRNA is anionic, hydrophilic, and easily degraded by nucleases in the body. As such, it cannot survive the harsh condition of the gastrointestinal (GI) tract or effectively penetrate the intestinal epithelia or membranes of target cells. Hence, an effective carrier is needed not only to protect siRNA from degradation in the GI tract but also to improve the intestinal absorption as well as transfection in macrophages, thereby maximizing the in vivo RNAi efficiency and anti-inflammatory effect of orally delivered siRNA.